This application addresses broad Challenge Area (05) Comparative Effectiveness and Specific Challenge Topic 05-DK-101* Selecting the Optimal Initial Treatment Regimen for Patients With Newly Discovered Type 2 Diabetes. Recommendations for initial pharmacotherapy in type 2 diabetes were modified in 2007 - to change from sulfonylureas to metformin as initial monotherapy, and from recommending an initial trial of medical nutrition therapy (MNT) and lifestyle change to recommending prompt initiation of pharmacotherapy along with MNT at initial diagnosis of diabetes. Findings from UKPDS and from two observational studies suggest that metformin monotherapy may lower risk for cardiovascular complications relative to sulfonylureas;findings from the ADOPT Study indicate that durability of monotherapy effectiveness is longer with metformin than with the sulfonylurea glyburide. Metformin also appears to have a modest relative benefit on LDL- cholesterol levels and usually does not cause hypoglycemia. Evidence from the Diabetes Prevention Program demonstrates that metformin is effective in preventing progression from impaired glucose tolerance to diabetes, suggesting that it may also be effective in slowing deterioration of pancreatic function once the diagnostic threshold for type 2 diabetes has been crossed if started immediately. Recent recommendations in response to the ACORD, ADVANCE, and VADT trials also suggest that early glycemic control may be more effective than later in preventing both microvascular and macrovascular complications of type 2 diabetes. These guidelines are acknowledged by their authors to be "consensus-based" and the need for better evidence, especially with respect to longer-term outcomes is clearly stated. They have not been widely adopted in clinical practice, and it is unknown whether they are impacting outcomes in diverse, real-world, patient populations. Undoubtedly, there has been variation in adoption across physicians, systems, and time, providing this "natural experiment" opportunity to study whether early initiation of metformin is superior to prior practice for delaying deterioration of diabetes and the onset of complications. We propose to examine the comparative effectiveness of immediate initiation of metformin monotherapy vs. delayed initiation of metformin or early/late initiation of sulfonylurea monotherapy for a variety of outcomes. Using electronic medical record data from 4 large health system members of the HMO Research Network Diabetes Consortium, we will create a large cohort of newly diagnosed type 2 diabetic patients with average follow-up of 3.5 years. In longitudinal analyses, we will examine whether prompt initiation of metformin (within 6 months of the earliest detection of diabetes) compared with other strategies is associated with: 1. Longer durability of glycemic control on monotherapy (from initial detection of diabetes to failure of monotherapy) 2. Less weight gain at 1 and 2 years post initial diagnosis 3. Differences in the incidence of severe hypoglycemia 4. Better LDL-cholesterol control or lower intensity of lipid-lowering therapy required 5. Differences in blood pressure control or lower intensity of anti-hypertensive therapy required 6. Differences in the incidence of cardiovascular disease endpoints (combined endpoint of acute myocardial infarction, stroke, or coronary, carotid or peripheral revascularization) 7. Differences in incidence of microvascular complications (new onset diabetic retinopathy, microalbuminuria, or rate of decline in estimated glomerular filtration rate). We recognize the risks of confounding inherent in observational approaches. Many clinical and demographic confounders are available to us from EMR records and all comparisons will be adjusted, using propensity scores, for these variables measured at or before initial detection of diabetes. As a complement to these analyses, we will conduct instrumental variable analyses, using physician prescribing practices as the instrumental variable. Recent studies suggest that metformin is the best oral medication for initial treatment of diabetes and that starting metformin immediately when diabetes is first detected, rather than waiting until blood sugars reach a somewhat higher target level, could delay progression of diabetes and prevent complications such as heart disease, stroke and kidney disease. This study compares very early treatment with metformin to more traditional approaches in a population of nearly 40,000 newly diagnosed diabetic patients from 4 large health care systems. If an advantage is shown for early use of metformin, the study's findings could dramatically change the way in which type 2 diabetes is treated in the U.S. and reduce the burden of complications from this very common condition.